Benzodioxole derivatives and pharmaceutical use thereof

ABSTRACT

The invention relates to novel benzodioxole derivatives of the formula I ##STR1## in which R 1  represents an unsubstituted or substituted, aromatic or heteroaromatic radical, alk represents an alkylene or alkylidene radical having a maximum of 5 carbon atoms, n represents 0 or 1, R 2  and R 3  each represents, independently of the other, hydrogen, lower alkyl, lower alkoxy or halogen, and A represents the radical O--R 4 , wherein R 4  represents hydrogen or an unsubstituted or substituted, aliphatic or araliphatic hydrocarbon radical, or A represents the radical ##STR2## in which either R 5  and R 6  each represents, independently of the other, hydrogen or lower alkyl, or R 5  and R 6  are bonded to one another and, together with the adjacent nitrogen atom, represent unsubstituted or lower alkyl-substituted tetra- or hexa-methyleneimino or 4-morpholinyl, to salts of compounds of the formula I in which A represents OR 4  wherein R 4  is hydrogen, with bases, and to acid addition salts of compounds of the formula I in which the radical R 1  has a basic character, and to pharmaceutical compositions that contain them. The novel substances exhibit diuretic and, in addition, uricosuric activity and may be administered, according to the invention, preferably in the form of appropriate pharmaceutical compositions, to mammals for the treatment of oedema and hypertension.

This invention relates to novel benzodioxole derivatives with valuablepharmacological properties, to pharmaceutical compositions containingthem, and to the use of these novel substances and pharmaceuticalcompositions.

The novel compounds according to the invention correspond to the formulaI ##STR3## in which R₁ represents an unsubstituted or substituted,aromatic or heteroaromatic radical,

alk represents an alkylene or alkylidene radical having a maximum of 5carbon atoms,

n represents 0 or 1,

R₂ and R₃ each represents, independently of the other, hydrogen, loweralkyl, lower alkoxy or halogen, and

A represents the radical --O--R₄, wherein R₄ represents hydrogen or anunsubstituted or substituted, aliphatic or araliphatic hydrocarbonradical, or A represents the radical ##STR4## in which either R₅ and R₆each represents, independently of the other, hydrogen or lower alkyl, orR₅ and R₆ are bonded to one another and, together with the adjacentnitrogen atom, represent unsubstituted or lower alkyl-substituted tetra-to hex-methyleneimino or 4-morpholinyl.

The novel compounds may be present in the form of racemates or opticalantipodes or, with the appropriate meanings for the variables,alternatively in the form of a mixture of racemates. The inventionrelates also to salts of compounds of the general formula I in which Arepresents OR₄ wherein R₄ represents hydrogen, with bases, and to acidaddition salts of compounds of the formula I in which the radical R₁ hasa basic character. Unless otherwise stated, hereinbefore and hereinafterlower radicals or compounds are to be understood as those having amaximum of 7, preferably a maximum of 4, carbon atoms.

An aromatic radical R₁ is especially a 1- or 2-naphthyl radical andespecially a phenyl radical. A heteroaromatic radical is preferably abicyclic radical and especially a monocyclic radical. As a correspondingmonocyclic radical, R₁ contains especially two nitrogen atoms or,preferably, one nitrogen atom and/or one oxygen or sulphur atom and isfor example, mono- or di-azacyclic, oxa- or thia-cyclic or oxaza- orthiazacyclic radical having 5 ring members, for example 1H-pyrrolyl,such as 1H-pyrrol-2-yl or -3-yl, 1H-pyrazolyl, such as 1H-pyrazol-3-yl,-4-yl or -5-yl, 1H-imidazolyl, such as 1H-imidazol-2-yl, -4-yl or -5-yl,furyl, such as 2- or 3-furyl, thienyl, such as 2- or 3-thienyl,oxazolyl, such as 2-oxazolyl, isoxazolyl, such as 3- or 5-isoxazolyl,thiazolyl, such as 2- or 4-thiazolyl, or a mono- or di-azacyclic radicalhaving 6 ring members, for example pyridyl, such as 2-, 3- or 4-pyridyl,pyridazinyl, such as 3-pyridazinyl, pyrimidinyl, such as 2-, 4- or5-pyrimidinyl, or 2-pyrazinyl. Corresponding bicyclic radicals R₁comprise, for example, a 5-membered hetero ring of aromatic characterhaving two nitrogen atoms or having one nitrogen atom and/or one oxygenor sulphur atom as ring members and a fused-on benzene ring, or a6-membered hetero ring of aromatic character having two or, especially,one nitrogen atom(s) as ring member(s) and a fused-on benzene ring.Accordingly, bicyclic heteroaryl is, for example, 1H-indolyl, such as1H-indol-2-yl, -3-yl, -4-yl, -5-yl or -6-yl, 1H-indazolyl, such as1H-indazol-3-yl, 1H-benzimidazolyl, such as 1H-benzimidazol-2-yl, -4-yl,-5-yl or -6-yl, benzofuranyl, such as 2-, 3-, 5- or 6-benzofuranyl,benzo[b]thienyl, such as benzo[b]thien-2-yl, -3-yl, -5-yl or -6-yl,benzoxazolyl, such as 2-, 4-, 5- or 6-benzoxazolyl, benzothiazolyl, suchas 2-, 4-, 5- or 6-benzothiazolyl, or, for example, quinolinyl, such as2-, 4-, 5- or 6-quinolinyl, isoquinolinyl, such as 1-, 3- or4-isoquinolinyl, quinazolinyl, such as 2-, 4- or 6-quinazolinyl,quinoxalinyl, such as 2- or 6-quinoxalinyl, or phthalazinyl, such as 1-or 6-phthalazinyl. As a substituted aromatic or heteroaromatic radical,R₁ is substituted once or several times, preferably a maximum of threetimes, for example by halogen, such as fluorine, bromine, iodide or,especially, chlorine, by lower alkyl, such as, for example, ethyl,propyl, isopropyl, butyl, isobutyl, tert.-butyl or, especially, methyl,and/or by lower alkoxy, such as ethoxy, propoxy, isopropoxy, butoxy,isobutoxy and, especially, methoxy and/or by trifluoromethyl.

An alkylene or alkylidene radical alk may be straightchain or branchedand is, for example, 1,1- or 2,2- or 1,2-dimethylethylene,1-ethylethylene, tetramethylene or 1-propylethylene or1-methylpropylidene, 2-methylpropylidene, butylidene or1-ethylpropylidene, but especially a radical containing a maximum of 3carbon atoms, such as ethylene, propylene, trimethylene or ethylidene,propylidene, or 1-methylethylidene and, especially, methylene.

R₂ and R₃ are, as lower alkyl, for example ethyl, propyl, isopropyl,butyl, isobutyl or tert.-butyl and, especially, methyl; as lower alkoxy,for example ethoxy, propoxy, isopropoxy, butoxy, isobutoxy and,especially, methoxy, and as halogen, bromine, iodine, especiallyfluorine or, more especially, chlorine. In a radical A, R₄ as anunsubstituted or substituted, aliphatic or araliphatic hydrocarbonradical is, for example, alkyl having a maximum of 12 carbon atoms,especially lower alkyl, also 2- or 3-lower alkenyl, or 2-lower alkynyl,lower alkoxy-lower alkyl, halogenated lower alkyl, such as geminalpolyhalo-lower alkyl, or, for example, phenyl-lower alkyl or cinnamyl inwhich the phenyl radical may be substituted, for example in the samemanner as a phenyl radical R₁. Alkyl R₄ is, for example, propyl,isopropyl, butyl, isobutyl, pentyl, isopentyl, neopentyl, hexyl, heptyl,octyl, nonyl, decyl, dodecyl and, especially, methyl or ethyl; loweralkenyl R₄ is, for example, allyl, 1- or 2-methallyl, 2-butenyl or3-butenyl; lower alkynyl is, for example, 2-propynyl; lower alkoxy-loweralkyl is especially 2- or 3-lower alkoxy-lower alkyl, such as, forexample, 2-methoxy-, 2-ethoxy-, 2-isopropoxy- or 2-butoxyethyl, 2- or3-methoxypropyl, 2- or 3-ethoxypropyl, also 3- or 4-methoxybutyl or 3-or 4-ethoxybutyl, and halogenated lower alkyl is especially geminally,that is to say at the same carbon atom, polyhalogenated lower alkyl,such as 2,2,2-trifluoro- or 2,2,2-trichloroethyl. Phenyl-lower alkyl R₄is, for example, benzyl, 2-phenylethyl, 2- or 3-phenylpropyl or 2-, 3-or 4-phenylbutyl.

Salts of the novel compounds are especially salts of compounds of thegeneral formula I in which A represents hydroxy, that is to say R₄represents hydrogen, with bases, especially pharmaceutically acceptablesalts of such compounds with bases. As such salts with bases there comeinto consideration, for example, alkali metal or alkaline earth metalsalts, such as sodium, potassium, calcium or magnesium salts, and alsoammonium salts with ammonia or organic amines, such as mono- or di-loweralkylamines, for example methylamine, ethylamine, dimethylamine ordiethylamine, or mono-, di- or tri(hydroxyalkyl)-amines, for example2-aminoethanol, 2,2'-iminodiethanol or 2,2',2"-nitrilotriethanol.

As acid addition salts, especially pharmaceutically acceptable acidaddition salts, of compounds of the general formula I in which R₁ is ofbasic character there come into consideration, for example, those withsuitable inorganic acids, such as hydrohalic acids, for examplehydrochloric acid or hydrobromic acid, and also nitric acid, sulphuricacid or phosphoric acid, or with suitable organic acids, such ascarboxylic acids, for example acetic acid, propionic acid, glycolicacid, succinic acid, maleic acid, hydroxymaleic acid, methylmaleic acid,fumaric acid, malic acid, tartaric acid, citric acid, benzoic acid,cinnamic acid, mandelic acid, salicylic acid, 4-aminosalicylic acid,2-phenoxybenzoic acid, 2-acetoxybenzoic acid, embonic acid, nicotinicacid or isonicotinic acid, or organic sulphonic acids, such as loweralkanesulphonic acids optionally containing hydroxy, for examplemethanesulphonic acid, ethanesulphonic acid, 2-hydroxyethanesulphonicacid or ethane-1,2-disulphonic acid, or arylsulphonic acids, for examplebenzenesulphonic acid, 4-methylbenzenesulphonic acid ornaphthalene-2-sulphonic acid, or other acidic substances, such asascorbic acid.

The novel compounds of the general formula I and their salts exhibitvaluable pharmacological properties. They have, in particular, adiuretic and naturetic action, in rats in a dosage range of from 10 to1000 mg/kg per os and in dogs in doses upwards from 20 mg/kg per os,which may be ascertained by collecting the urine over a period of 3hours after administration (rats) and hourly over a period of 5 hoursafter administration (dogs) and determining the volume of urine and ofsodium, potassium and chlorine ions. In this case the excretion ofpotassium is increased to a lesser extent than is the excretion ofsodium; the good tolerability should also be emphasised.

For example, the administration to rats of 10 mg/kg per os of5-[(4-fluorophenyl)-acetyl]-6-methyl-2-benzodioxolecarboxylic acid or 10mg/kg per os of 5-methyl-6-(2-thienylcarbonyl)-2-benzodioxolecarboxylicacid (3 animals per dose), in comparison with untreated control animals,increases the excretion of sodium ions by a factor of 3.6 and 2.6,respectively; of potassium ions by a factor of 2.2 and 2.4,respectively, and of chlorine ions by a factor of 2.6 and 2.3,respectively. In dogs, for example the administration of 20 mg/kg per osof 5-benzoyl-6-methyl-2-benzodioxolecarboxylic acid (3 animals per dose)increases the average excretion per minute measured during the first 3or the first 5 hours after administration, in comparison with theaverage excretion per minute during the hour before administration, withregard to sodium ions by a factor of 8 and 5.5, respectively; withregard to potassium ions by a factor of only 1.2 and not at all,respectively; with regard to chlorine ions by a factor of 9 and 6,respectively, and with regard to the volume of urine by a factor of 2.8and 2.2, respectively. In dogs, the excretion of potassium is thusscarcely increased by this carboxylic acid.

Furthermore, the compounds of the general formula I exhibit uricosuricactivity, as can be seen, for example, from experiments on Cebus apes(Cebus apella). In these experiments the test animals, underpentobarbital narcosis, are given, by intravenous infusion,polyfructosane in Ringer solution and the test substance in the form ofan aqueous solution is injected intravenously in doses of increasingsize. Urine is collected for three 10 minute periods before the firstadministration of test substance and then after each dose of testsubstance, and arterial blood is removed before the first collectionperiod and after the last collection period. The uric acid andpolyfructosane clearance is calculated from their plasma and urineconcentration and finally the fractional excretion of uric acid FE_(UR)is determined as a quotient of the uric acid clearance and glomerularfiltration rate. In this test, compounds of the general formula Iexhibit activity in a dosage range of from 1 to 10 mg/kg i.v.; forexample the administration of 10 mg/kg of5-benzoyl-6-methyl-2-benzodioxolecarboxylic acid effects almost adoubling of the fractional excretion of uric acid. Accordingly, thecompounds of the general formula I and their pharmaceutically acceptablesalts can be used as potassium-sparing diuretics having supplementaryuricosuric action, for example for the treatment of oedema andhypertension.

The invention relates especially to compounds of the general formula Iin which R₁ represents phenyl, thienyl or furyl, each of which isunsubstituted or substituted by lower alkyl, lower alkoxy or halogen,alk represents alkylene or alkylidene having a maximum of 3 carbonatoms, R₂ represents lower alkyl or halogen, R₃ represents hydrogen,lower alkyl or halogen; and n and A have the meanings given underformula I, but A represents especially OR₄ and therein R₄ representshydrogen or lower alkyl, and salts of those compounds in which R₄represents hydrogen with bases.

The invention relates more especially to compounds of the generalformula I in which R₁ represents phenyl or thienyl, each of which isunsubstituted or substituted by lower alkyl, lower alkoxy or halogen,alk represents methylene, n represents 0 or 1, R₂ represents loweralkyl, especially methyl, or halogen, especially fluorine or chlorine,R₃ represents hydrogen or lower alkyl, especially methyl, and Arepresents OR₄ wherein R₄ represents hydrogen or lower alkyl, and thepharmaceutically acceptable salts of those compounds in which R₄represents hydrogen with bases.

The invention relates most especially to compounds of the generalformula I in which R₁ represents phenyl that is unsubstituted orsubstituted by lower alkyl, lower alkoxy or halogen, alk representsmethylene, n represents 0 or 1, R₂ represents lower alkyl, especiallymethyl, or halogen, especially fluorine or chlorine, R₃ representshydrogen or lower alkyl, especially methyl, and A represents OR₄ whereinR₄ represents hydrogen or lower alkyl, and the acyl radical ispreferably bonded in the 5- or 6-position, and the pharmaceuticallyacceptable salts of those compounds in which R₄ represents hydrogen withbases.

The invention relates above all to compounds of the general formula I inwhich R₁ represents phenyl substituted by lower alkyl, especiallymethyl, lower alkoxy, especially methoxy, or halogen, especiallyfluorine, but is especially unsubstituted phenyl, alk representsmethylene, n represents 1 or, especially, O, R₂ represents lower alkyl,especially methyl, or halogen, especially fluorine or chlorine, R₃represents hydrogen, and A represents OR₄ wherein R₄ represents hydrogenor lower alkyl, and the acyl radical is bonded in the 5- or 6-position,and the pharmaceutically acceptable salts of those compounds in which R₄represents hydrogen with bases, such as the three carboxylic acidsmentioned specifically above, and their pharmaceutically acceptablesalts with bases.

The novel compounds of the general formula I and salts of thosecompounds in which A represents OR₄ wherein R₄ is hydrogen, or that havea basic character, are manufactured in a manner known per se, by

(a) reacting a compound of the general formula II ##STR5## in which R₁,alk, n, R₂ and R₃ have the meanings given under formula I, or a saltthereof, with a compound of the general formula III ##STR6## in whichHal represents halogen and A has the meaning given under formula I, orwith a salt of such a compound in which A represents OR₄ wherein R₄represents hydrogen, or

(b) in a compound of the general formula IV ##STR7## in which A^(b)represents carboxy, lower alkoxycarbonyl or acetyl, and R₁, alk, n, R₂,R₃ and A have the meanings given under formula I, replacing the radicalA^(b) by hydrogen, or

(c) for the manufacture of a compound of the general formula I in whichA has the meaning given under formula I with the exception of a radicalOR₄ in which R₄ represents hydrogen, and R₁, alk, n, R₂ and R₃ have themeanings given under formula I, reacting a compound of the generalformula V ##STR8## with an anhydride of a compound of the generalformula VI

    R.sub.1 --(alk).sub.n --CO--OH                             (VI),

in which A₁ has the meaning given for A under formula I with theexception of a radical OR₄ in which R₄ represents hydrogen, and R₂ andR₃ and R₁, alk and n have the meanings given under formula I, or

(d) for the manufacture of a compound of the general formula I in whichA represents OR₄ wherein R₄ represents hydrogen, and R₁, alk, n, R₂ andR₃ have the meanings given under formula I, or a salt of this compound:in a compound of the general formula VII ##STR9## in which A^(d)represents a group that can be converted into the carboxy group and R₁,alk, n, R₂ and R₃ have the meanings given under formula I, convertingthe group A^(d) into the carboxy group in free or salt form, or

(e) for the manufacture of a compound of the general formula I in whichA has the meaning given under formula I with the exception of a radicalOR₄ in which R₄ represents hydrogen, and R₁, alk, n, R₂ and R₃ have themeanings given under formula I: in a compound of the general formulaVIII ##STR10## in which A^(e) represents a radical that can be convertedinto a radical --CO--A₁, in which A₁ has the meaning given for A underformula I with the exception of a radical OR₄ in which R₄ representshydrogen, and R₁, alk, n, R₂ and R₃ have the meanings given underformula I, converting the radical A^(e) into the radical --CO--A₁, and,if desired, converting a resulting compound of the general formula I ina manner known per se into a different compound of the general formulaI, and/or separating a compound of the general formula I obtained in theform of a racemate into the optical antipodes, and/or converting aresulting compound of the general formula I in which A represents OR₄wherein R₄ represents hydrogen into a salt with a base or freeing such acompound from a resulting salt, or converting a resulting compound ofthe general formula I having basic character into an acid addition saltor freeing such a compound from a resulting salt.

In the starting materials of the general formula III, Hal is preferablychlorine or bromine, but may also be fluorine or iodine, it also beingpossible for two different halogen atoms to be present. The reactionsaccording to process (a) are preferably carried out in organic solventsthat are inert under the reaction conditions, for example etherealsolvents, such as, for example, dibutyl ether, 1,2-dimethoxyethane,diethyleneglycol dimethyl ether, tetrahydrofuran or dioxan; alcoholicsolvents, such as, for example, methanol, ethanol, isopropanol, butanol,2-methoxyethanol or 2-ethoxyethanol; or amide-type solvents, such as,for example, dimethylformamide or N,N,N',N',N",N"-hexamethylphosphoricacid triamide; or in hydrocarbons, such as, for example, petroleumether, cyclohexane, benzene or toluene. Reactions with free compounds ofthe general formula II and also with free haloacetic acids of thegeneral formula III are preferably carried out in the presence of basicsubstances. As such basic substances there may be used, for example,organic or inorganic derivatives of alkali metals or alkaline earthmetals: as organic derivatives, there may be used, for example, alkalimetal or alkaline earth metal alkoxides, such as sodium or lithiummethoxide, ethoxide, n-butoxide or tert.-butoxide, or barium methoxide,and as inorganic derivatives, for example, corresponding hydroxides,such as, for example, sodium, potassium or calcium hydroxide, orcarbonates, such as, for example, sodium or potassium carbonate. Inparticular carbonates may be used in relatively large excess, forexample up to 5-fold excess. When using carbonates, also other organicsolvents, such as lower alkanones, for example acetone or 2-butanone,may come into consideration as being sufficiently inert.

Suitable salts of compounds of the general formula II and ofdihaloacetic acids falling within the scope of the general formula IIIwhich may be used are, for example, corresponding alkali metal salts oralkaline earth metal salts. The reaction temperatures are, for example,between room temperature and approximately 150° C. and preferablybetween approximately 70° and 120° C.

Some of the starting materials of the general formulae II and III areknown and others may be manufactured analogously to the known compounds.Thus, for example, starting materials of the general formula I may bemanufactured by firstly condensing veratrole, which can be substitutedin a manner corresponding to the definition for R₂ and R₃, with an acylhalide derived from a carboxylic acid of the formula R₁ --COOH or R₁--alk--COOH, according to the Friedel-Crafts method, for example, bymeans of aluminium chloride in 1,2-dichloroethane at room temperature,to form the corresponding ketone, and cleaving the two methoxy groups inthis ketone in a manner know per se, for example by heating withpyridine hydrochloride or with 48% hydrobromic acid in acetic acid. Ifstarting materials of the formula II are required in which alkrepresents a lower alkylidene radical, but especially a 1-loweralkylalkylidene radical, such as the 1-methylethylidene radical, it ispossible, after the Friedel-Craft condensation and before the cleavageof the methoxy groups, to introduce into a keto compound in which alkrepresents methylene or lower alkylidene, one or preferably two loweralkyl, or one lower alkyl respectively, especially methyl, by reactionwith a lower alkyl halide, such as methyl iodide, for example in atwo-phase system comprising a concentrated aqueous solution oftetrabutylammonium hydroxide or bromide and an inert organic solvent,for example methylene chloride.

To carry out process (b), for example a starting material of the generalformula IV in which A^(b) represents carboxy and A, R₁, R₂ and R₃ havethe meanings given under formula I is heated in the presence or absenceof a catalyst, for example copper powder, and/or in the presence of asolvent or diluent, such as, for example, o-dichlorobenzene or1,2,3,4-tetrahydronaphthalene, until at least an almost equimolar amountof carbon dioxide has been liberated. Starting materials of the generalformula IV in which A^(b) represents carboxy and A represents OR₄wherein R₄ represents hydrogen are manufactured, for example, byhydrolysis of corresponding compounds in which the substituent in thecorresponding position to A is OR₄ wherein R₄ represents lower alkyl,and the substituent in the corresponding position to A^(b) is loweralkoxycarbonyl or cyano, in acidic or alkaline medium, for example byheating with a strong mineral acid in an aqueous or aqueous-organic, forexample aqueous-lower alkanolic, medium, or with at least twice themolar amount of an alkali metal hydroxide, especially sodium orpotassium hydroxide, for example in a lower alkanol, such as methanol,ethanol, isopropanol or n-butanol, or in a lower alkanediol or monoalkylether thereof, for example ethyleneglycol, 2-methoxyethanol or2-ethoxyethanol, with water optionally being added to the above solventsin a volume ratio of water to solvent of about 1:10 to 2:1. Water mayalso be used as the reaction medium or, for example, a mixture of waterand water-soluble, ethereal solvents, such as dioxan or tetrahydrofuran.

If the hydrolysis is effected in a water-containing mineral acid, thedecarboxylation according to the process may be carried outsubsequently, that is to say, in the same medium and operation.

Starting materials of the general formula IV in which A^(b) representscarboxy and A represents a radical corresponding to the definition givenunder formula I with the exception of a radical OR₄ in which R₄represents hydrogen, can be manufactured, for example, by analogoushydrolysis in alkaline medium of corresponding compounds having loweralkoxycarbonyl as the radical A^(b) using an approximately equimolaramount of an alkali metal hydroxide instead of at least twice the molaramount. Another possibility for the manufacture of such startingmaterials of the general formula IV consists in the hydrogenolysis ofcorresponding compounds which contain benzyloxycarbonyl in the A^(b)position.

The dealkoxycarbonylation or deacetylation of corresponding startingmaterials of the general formula IV, that is to say, those in whichA^(b) represents lower alkoxycarbonyl or acetyl and A represents aradical according to the definition with the exception of a radical OR₄in which R₄ represents hydrogen, is effected, for example, by reactionwith an approximately equimolar amount of an alkali metal-lower alkoxidein an anhydrous lower alkanol, and if A represents a radical OR₄ inwhich R₄ represents lower alkyl, it is preferable to select the samelower alkanol, for example methanol, ethanol or n-butanol, both ascomponent of the starting ester and of the lower alkoxide and asreaction medium. It is also possible, however, to carry out atransesterification by using as reaction medium a relativelyhigh-boiling alkanol that is not the same as the lower alkanol presentas the ester component and distilling off a portion thereofsimultaneously with the reaction according to the definition or to allowfor only a partial transesterification if the ester of the generalformula I formed as a reaction product is not to be used directly asactive ingredient but is to be hydrolysed to form the correspondingacid. Instead of a lower alkanol it is also possible to use as reactionmedium, for example, an inert organic solvent, such as, for example,benzene or toluene. The reaction according to the definition is carriedout at room temperature or at elevated temperature, for example at theboiling temperature of the reaction medium used. If required, theresulting ester of the general formula I may, as already mentioned inconnection with the transesterification, be hydrolysed to form thecorresponding acid in the same operation if water is added to thereaction medium.

The starting materials of the general formula IV in which A^(b)represents lower alkoxycarbonyl or acetyl, and the above-mentionedprecursors for compounds of the general formula IV containing carboxy asradical A^(b) that contain lower alkoxycarbonyl or cyano in the A^(b)position, can be manufactured analogously to process (a) by reactingcompounds of the general formula II with geminal dihalo compounds thatdiffer from those of the general formula III by the presence of loweralkoxycarbonyl, acetyl or cyano in place of the hydrogen atom locatedadjacent to two halogen atoms, in the presence of a base.

For process (c) there are used as anhydrides of compounds of the generalformula VI, for example, the halides thereof, such as chlorides orbromides, and also, for example, symmetrical anhydrides thereof.Suitable catalysts for the reaction are, for example, those forcustomary Friedel-Crafts condensations, such as aluminium chloride ortin(IV) chloride, and also, for example, zinc chloride, concentratedsulphuric acid, phosphoric acid, polyphosphoric acid or pyrophosphoricacid. The above-mentioned acids are preferably used when there is usedas derivative of a carboxylic acid of the general formula VI asymmetrical carboxylic acid anhydride. The reaction is preferablycarried out in a solvent. As such solvents there may be used, forexample, halogenated hydrocarbons, such as 1,2-dichloroethane, carbontetrachloride, methylene chloride or o-dichlorobenzene, and also, forexample, aliphatic or cycloaliphatic hydrocarbons, such as heptane orcyclohexane, nitrohydrocarbons, such as nitromethane, nitrocyclohexaneor nitrobenzene, and also, under mild conditions, also carbondisulphide. The reaction temperature is between approximately -20° C.and +80° C., preferably between approximately 0° and room temperature.

The starting materials of the general formula V may, for their part, bemanufactured analogously to process (a) from pyrocatechol optionallysubstituted in a manner corresponding to the definition for R₂ and R₃,such as, for example, homopyrocatechol (4-methylpyrocatechol) withdihaloacetic acids or functional derivatives thereof corresponding tothe general formula III. Some of the functional derivatives of compoundsof the general formula VI required as second reactant are known andothers may be manufactured analogously to the known derivatives.

In the manufacture of compounds of the general formula I in which Arepresents the radical OR₄ wherein R₄ represents hydrogen, according toprocess (d) the conversion of a group A^(d) into the carboxy group canbe effected in a manner known per se, especially by hydrolysis in analkaline or acidic medium, it being possible in the former case toobtain a salt also directly. Starting materials for the hydrolysis arein the first instance those compounds of the general formula I in whichA is not a radical OR₄ in which R₄ represents hydrogen, especially thosecompounds which can readily be hydrolysed, such as, for example, thelower alkyl esters, but also other functional derivatives of thecarboxylic acids desired as end products, such as, for example, nitrilesand imido esters, especially imido-lower alkyl esters, of carboxylicacids falling within the scope of the general formula I. The hydrolysisis effected, for example, in lower alkanolic or aqueous-lower alkanolicalkali hydroxide solutions from room temperature to approximately 100°C. or the boiling temperature of the reaction medium. Lower alkylesters, such as methyl or ethyl esters, and other readily cleavableesters of the carboxylic acids falling within the scope of the generalformula I can be hydrolysed under even milder conditions, for example inthe presence of potassium or sodium carbonate at room temperature or, ifnecessary, at a slightly elevated temperature, for example 40° C., in anaqueous-organic medium, for example by adding water to the reactionmixture obtained in the reaction according to (a) in a water-misciblesolvent, such as, for example, 1,2-dimethoxyethane. From the alkalimetal salt solutions of the carboxylic acids falling within the scope ofthe general formula I, which solutions are obtained first of all, it ispossible either to obtain the corresponding pure alkali salt directly byconcentration and filtration or total evaporation of the solvent andrecrystallisation, or to free the carboxylic acid first of all and thento purify it, for example by recrystallisation and, if desired, convertit into a salt again with a suitable inorganic or organic base.Functional derivatives of the carboxylic acids falling with the scope ofthe general formula I may also be converted into the free carboxylicacid of the general formula I in an acidic medium, for example byheating in sulphuric acid diluted with water, for example 60-70%sulphuric acid, or in lower alkanolic-aqueous hydrochloric acid.

The required functional derivatives of carboxylic acids that fall withinthe scope of the general formula I are manufactured, for example,according to process (a), (b) or (c), and other functional derivatives,such as, for example, nitriles, are manufactured analogously to theseprocesses.

Starting materials of the general formula VIII are, according to thenature of the radical A^(e) they contain, for example, carboxylic acids,carboxylic acid halides or anhydrides, especially mixed anhydrides, andalso activated esters, for example cyanomethyl esters, and also loweralkyl esters, which can be reacted, optionally in the presence ofcondensation agents, with hydroxy compounds of the general formula IX

    R.sub.4 --OH                                               (IX)

or ammonia or amines of the general formula X ##STR11## in whichformulae R₄, R₅ and R₆ have the meanings given under formula I, orsalts, especially alkali metal or alkaline earth metal salts, of freecarboxylic acids, which can be reacted with reactive esters of hydroxycompounds of the general formula IX, such as halides, or organicsulphonic acid esters, for example lower alkanesulphonic orarenesulphonic acid esters, such as methanesulphonic orp-toluenesulphonic acid esters, or alternatively with carbamic acidhalides, especially chlorides, derived from amines of the generalformula X in which the radicals R₅ and R₆ are other than hydrogen; andalso, for example, the imido esters, especially imido-lower alkylesters, or nitriles, that can be hydrolysed to form esters, especiallylower alkyl esters, and to form unsubstituted amides, respectively. Freecarboxylic acids can be reacted, for example, also with diazo-loweralkanes to form lower alkyl esters, or with isocyanates that are derivedfrom primary amines falling within the scope of the general formula X,to form N-mono-substituted amides.

The reactions of free carboxylic acids with hydroxy compounds of thegeneral formula IX are effected advantageously in the presence of anacidic water-removing catalyst, such as a protonic acid, for example inthe presence of hydrochloric or hydrobromic acid, sulphuric acid,phosphoric acid or boric acid, benzenesulphonic or toluenesulphonicacid, or a Lewis acid, for example boron trifluoride etherate, in anexcess of the hydroxy compound used and/or in an inert solvent, forexample in a hydrocarbon of the benzene series, such as benzene ortoluene, a halogenated hydrocarbon, such as chloroform, methylenechloride or chlorobenzene, or in an ethereal solvent, such astetrahydrofuran, if necessary with removal by distillation, for exampleazeotropic, of the water freed in the reaction. It is also possible tocarry out the reactions in the presence of other water-bindingcondensation agents, for example in the presence of carbodiimidessubstituted by hydrocarbon radicals, such as N,N'-diethyl-,N,N'-dicyclohexyl- or N-ethyl-N'-(3-dimethylaminopropyl)-carbodiimide,in inert organic solvents, for example those mentioned above. Halidesand mixed anhydrides are reacted, for example, in the presence ofacid-binding agents, for example organic, especially tertiary, nitrogenbases, such as, for example, triethylamine, ethyl diisopropylamine orpyridine, or alternatively inorganic bases, for example, alkali metal oralkaline earth metal hydroxides or carbonates, such as sodium, potassiumor calcium hydroxide or carbonate, in inert organic solvents, forexample those mentioned above, and, if necessary, while heating. Thereactions of reactive esters of carboxylic acids of the general formulaI, for example the cyanomethyl esters, with hydroxy compounds of thegeneral formula IX are carried out, for example, in a solvent that isinert towards the reactants, for example in a hydrocarbon, such astoluene or xylene, an ethereal solvent, such as tetrahydrofuran ordioxan, or alternatively, at moderate temperatures, in an ester, such asethyl acetate, in a temperature range of from approximately 0° toapproximately 120° C., preferably from room temperature to approximately60° C. For the transesterification of lower alkyl esters of carboxylicacids of the general formula I it is preferable to use hydroxy compoundsof the general formula IX having a boiling point clearly above that ofthe esterified lower alkanol and to carry out the reaction, for example,in an excess of the hydroxy compound and/or in an inert organic solventthat preferably also has a boiling point clearly higher than that of thelower alkanol, preferably in the presence of a catalyst, for example analkali metal-lower alkoxide, such as sodium or potassium methoxide orethoxide, at elevated temperature and, preferably, while distilling offthe lower alkanol that is liberated. The hydrolysis of imido esters,especially of imido-lower alkyl esters, of carboxylic acids of thegeneral formula I is effected, for example, by means of awater-containing mineral acid, such as hydrochloric or sulphuric acid;and imido ester hydrochlorides obtained, for example, by the addition ofhydrogen chloride to nitriles and reaction with anhydrous hydroxycompounds of the general formula IX, especially lower alkanols, can,after the addition of water, be hydrolysed directly to the correspondingesters, or, for example, the corresponding ester of the general formulaI can also be obtained from a mixture of nitrile, hydroxy compound andsulphuric acid having a suitable water content, without isolating theimido ester formed in situ.

The reaction of free carboxylic acids of the general formula I withcompounds of the general formula X is effected, for example, in thepresence of the above-mentioned water-binding agents and in theabove-mentioned inert organic solvents, but it is also possible toconvert the ammonium salts formed first of all from the free carboxylicacids and the compounds of the general formula X into amides of thegeneral formula I by heating, optionally in a suitable organic solenthaving a medium or high boiling point, such as, for example, xylene,chlorobenzene or 1,2,3,4-tetrahydronaphthalene, and removal bydistillation, optionally azeotropic, of the water liberated in thereaction.

As reactive functional derivatives of carboxylic acids of the generalformula I for the reaction with compounds of the general formula X andas associated condensation agents and solvents there come intoconsideration substantially the same derivatives, condensation agentsand solvents as those indicated above for reactions with hydroxycompounds of the general formula IX, except that as acid-binding agentsand optionally as the only reaction medium, it is possible to useinstead of other bases, i.e. tertiary organic bases, alternatively anexcess of the compound of the general formula X to be reacted. Thepartial hydrolysis of the corresponding nitriles, mentioned above as afurther possibility for forming N-unsubstituted amides, may be carriedout, for example, by means of water-containing mineral acids, such ashydrochloric acid or dilute sulphuric acid, at room temperature or atmoderately elevated temperature.

The free carboxylic acids of the general formula I required as startingmaterials for process (e) can be manufactured according to processes(a), (b), (c) and/or (d), and the reactive functional derivativesthereof can be manufactured, for example, from the free carboxylicacids, in a manner known per se.

Resulting salt-forming compounds of the formula I can be converted intosalts in a manner known per se; for example, those with hydroxy asradical A may be converted with corresponding bases, such as, forexample, alkali metal hydroxides, into salts with bases, or those havinga basic character may be converted into their acid addition salts.Preferably pharmaceutically acceptable salts are manufactured.

Resulting salts can be converted into the free compounds in a mannerknown per se, for example by treatment with an acidic reagent, such as amineral acid, or with a base, for example an alkali metal hydroxidesolution, such as sodium hydroxide solution.

The compounds, and their salts, can also be obtained in the form oftheir hydrates, or their crystals may include the solvent used forcrystallisation.

As a result of the close relationship between the novel compounds of thegeneral formula I in which A represents hydroxy in free form and in theform of their salts with bases, and between those compounds in which theradical R₁ has basic character in free form and in the form of acidaddition salts, hereinbefore and hereinafter the free compounds andtheir salts shall be understood to mean optionally also thecorresponding salts and free compounds, respectively, where appropriatewith regard to meaning and purpose.

Depending upon the number of centres of asymmetry and upon the startingmaterials and procedures chosen, the novel compounds may be obtained inthe form of racemates or mixtures of racemates (mixtures ofdiastereoisomers) or, where desired, also in the form of pure antipodes.

Resulting mixtures of racemates may be separated into the pure racematesor diastereoisomers in known manner, on the basis of the physicochemicaldifferences between the constituents, for example by chromatographyand/or fractional distillation. Resulting racemates may also beseparated into the optical antipodes according to known methods, forexample by recrystallisation from an optically active solvent, with theaid of micro-organisms or by reaction of an acidic end product of thegeneral formula I with an optically active base that forms salts withthe racemic acid, or by reaction of a basic end product of the generalformula I with an optically active acid, and separating the saltsobtained in this manner, for example on the basis of differingsolubility, into the diastereoisomers, from which the antipodes may befreed by the action of suitable agents. Advantageously the more activeof the two antipodes is isolated.

The invention relates also to those embodiments of the process accordingto which a compound obtainable as an intermediate at any stage of theprocess is used as starting material and the remaining process steps arecarried out, or a starting material is used in the form of a salt and/orracemate or antipode, or, especially, is formed under the reactionconditions.

The starting materials used in the processes of the present inventionare preferably those which result in the compounds described at thebeginning as being especially valuable. The present invention relatesalso to novel starting materials and to processes for their manufacture.

The invention relates also to pharmaceutical compositions that containcompounds of the general formula I as active ingredients, and toprocesses for their manufacture.

The pharmaceutical compositions according to the invention are forenteral, such as oral or rectal, and for parenteral administration towarm-blooded animals. The dosage of the active ingredient, which may beadministered alone or together with a customary carrier or adjunct,depends upon the species of warm-blooded animal, age and individualcondition and upon the method of administration. The daily doses arebetween 0.5 and 30 mg/kg for mammals, the daily dose for a mammalweighing approximately 70 kg preferably being between 25 and 900 mg,especially between 50 and 600 mg, depending on individual condition andage. Appropriate oral dosage unit forms, for example dragees, tablets orcapsules, contain preferably from 12.5 to 300 mg, especially from 25 to200 mg, of an active ingredient according to the invention, that is tosay, a compound of the general formula I or a pharmaceuticallyacceptable salt of a compound of the general formula I that is capableof salt formation, together with pharmaceutical carriers.

The pharmaceutical compositions of the present invention aremanufactured in a manner known per se, for example by means ofconventional mixing, granulating, confectioning, dissolving orlyophilising processes. For example, pharmaceutical compositions fororal use can be obtained by combining the active ingredient with solidcarriers, optionally granulating a resulting mixture and processing themixture or granulate, if desired, or necessary after the addition ofsuitable adjuncts, to form tablets or dragee cores.

Suitable carriers are especially fillers, such as sugar, for example,lactose, saccharose, mannitol or sorbitol, cellulose preparations and/orcalcium phosphates, for example tricalcium phosphate or calciumbiphosphate, also binders, such as starch pastes using, for example,maize, wheat, rice or potato starch, gelatine, tragacanth,methylcellulose and/or polyvinylpyrrolidone, and/or, if desired,disintegrators, such as the above-mentioned starches, also carboxymethylstarch, crosslinked polyvinylpyrrolidone, agar, alginic acid or a saltthereof, such as sodium alginate. Adjuncts are especiallyflow-regulating agents and lubricants, for example silica, talc, stearicacid or salts thereof, such as magnesium stearate or calcium stearate,and/or polyethylene glycol. Dragee cores are provided with suitablecoatings that are optionally resistant to gastric juices, there beingused, inter alia, concentrated sugar solutions which may contain gumarabic, talc, polyvinylpyrrolidone, polyethylene glycol and/or titaniumdioxide, lacquer solutions in suitable organic solvents or solventmixtures or, for the production of coatings that are resistant togastric juices, solutions of suitable cellulose preparations, such asacetylcellulose phthalate or hydroxypropylmethylcellulose phthalate.Dyes or pigments can be added to the tablets or dragee coatings, forexample for identification purposes or to indicate different doses ofactive ingredient.

Further pharmaceutical dose units for oral administration are dry-filledcapsules consisting of gelatine and also soft sealed capsules consistingof gelatine and a plasticiser, such as glycerine or sorbitol. Thedry-filled capsules may contain the active ingredient in the form of agranulate, for example in admixture with fillers, such as lactose,binders, such as starches, and/or glidants, such as talc or magnesiumstearate, and optionally stabilisers. In soft capsules, the activeingredient is preferably dissolved or suspended in suitable liquids,such as fatty oils, paraffin oil or liquid polyethylene glycols, itbeing possible also to add stabilisers.

As rectally administrable pharmaceutical compositions there come intoconsideration, for example, suppositories which consist of a combinationof the active ingredient with a suppository base. Suitable suppositorybases are, for example, natural or synthetic triglycerides, paraffinhydrocarbons, polyethylene glycols and higher alkanols. It is alsopossible to use gelatine rectal capsules which contain a combination ofthe active ingredient with a base material; as base materials there comeinto consideration, for example, liquid triglycerides, polyethyleneglycols and paraffin hydrocarbons.

Especially suitable for parenteral administration are aqueous solutionsof an active ingredient in water-soluble form, for example awater-soluble salt, also suspensions of the active ingredient, such ascorresponding oily injection suspensions, there being used suitablelipophilic solvents or vehicles, such as fatty oils, for example sesameoil, or synthetic fatty acid esters, for example ethyl oleate ortriglycerides, or aqueous injection suspensions that contain substanceswhich increase the viscosity, for example sodium carboxymethylcellulose,sorbitol and/or dextran, and, optionally, also stabilisers.

The invention relates also to the use of the novel compounds of theformula I and the pharmaceutically acceptable salts thereof aspharmacologically active compounds, especially as diuretics havingsupplementary uricosuric action, preferably in the form ofpharmaceutical compositions in a method for the prophylactic and/ortherapeutic treatment of the human or animal body, especially for thetreatment of oedema and/or hypertension.

The following Examples illustrate the invention described above but arenot intended to limit its scope in any way. Temperatures are given indegrees Centigrade.

EXAMPLE 1

While stirring at 5° to 10°, 33.3 g (0.25 mol) of aluminium chloride areadded in portions over a period of 30 minutes to a solution of 20.8 g(0.1 mol) of 5-methyl-2-benzodioxolecarboxylic acid ethyl ester and 16.9g (0.12 mol) of benzoyl chloride in 250 ml of 1,2-dichloroethane and themixture is stirred for a further 30 minutes at 5° to 10° and then heatedto room temperature. It is then poured onto a mixture of approximately500 g of ice and approximately 1000 ml of water. There is first formedan emulsion from which the organic phase gradually separates out. Thisis separated off and washed in succession twice with 100 ml of watereach time, once with 200 ml of 2 N sodium carbonate solution and twicewith 100 ml of water. The combined aqueous phases are in turn extractedtwice with 100 ml of chloroform each time and the residue from theseextracts is combined with the organic phase. The latter is then driedwith sodium sulphate, filtered and concentrated by evaporation. Thecrude 5-benzoyl-6-methyl-2-benzodioxolecarboxylic acid ethyl ester thatremains is purified by column chromatography on 1000 g of silica gelusing chloroform/petroleum ether/ethyl acetate in the ratio 10:10:1 assolvent and eluant. After first-run fractions of approximately 7 to 10%of the total amount, the above-mentioned ester is obtained as a mainproduct of viscous consistency which can be further used directly.

14.2 g (0.05 mol) of 5-benzoyl-6-methyl-2-benzodioxolecarboxylic acidethyl ester are dissolved in 160 ml of ethanol, 120 ml of 2 N sodiumhydroxide solution are added and the mixture is stirred at roomtemperature for 30 minutes. The ethanol is then evaporated off underreduced pressure, a small quantity of fuller's earth is added to thealkaline solution that remains and the whole is filtered with suction.150 ml of 2 N hydrochloric acid are added to the filtrate and the acidthat separates out is extracted with approximately 800 ml of ethylacetate and then twice more with 100 ml of ethyl acetate each time. Theorganic phases are combined, washed twice with 100 ml of water eachtime, dried with sodium sulphate, filtered and concentrated byevaporation. The residue is dissolved in a small quantity of ether andpetroleum ether is added to the solution until it becomes turbid. Animpurity separates out which, after the addition of a small quantity offuller's earth, is filtered off. The clear yellow filtrate isconcentrated by evaporation, dissolved in 25 ml of ethyl acetate andagain filtered. Cyclohexane is added to the filtrate until it becomesturbid and the filtrate is inoculated with the desired acid, ifavailable, yielding 5-benzoyl-6-methyl-2-benzodioxolecarboxylic acidhaving a melting point of 119°-122°. Further reaction product can beobtained from the residue of the mother liquors by dissolving in ethylacetate and adding cyclohexane as above.

The 4-methyl-2-benzodioxolecarboxylic acid ethyl ester used as startingmaterial is manufactured as follows:

(a) 124 g (1 mol) of homopyrocatechol (4-methylpyrocatechol) areintroduced at approximately 15° over a period of 10 minutes into asodium ethoxide solution, prepared in customary manner by dissolving46.0 g (2 mol) of sodium in 1500 ml of absolute ethanol under dry,oxygen-free nitrogen and with the exclusion of water, and a darksolution that is blue at the surface is formed. 157 g (1 mol) ofdichloroacetic acid ethyl ester are then added dropwise at approximately10° over a period of 20 minutes. The reaction mixture is then stirred atroom temperature for one hour and then boiled under reflux for 6 hours.10 g of "silica gel H according to Stahl" are added, while stirring, tothe resulting dark-brown solution and the whole is filtered throughdiatomaceous earth. The dark-brown filtrate is concentrated byevaporation in vacuo and the black, viscous residue is dissolved insufficient ether and 300 ml of 5% sodium bicarbonate solution; the etherphase is first extracted with sodium bicarbonate solution and then, inorder to remove any homopyrocatechol still present, extracted 6 timeswith 50 ml of 2 N sodium hydroxide solution each time, and finally iswashed twice with water, dried over sodium sulphate, filtered andconcentrated by evaporation in a rotary evaporator. The red liquid thatremains is distilled in vacuo, the desired5-methyl-2-benzodioxolecarboxylic acid ethyl ester passing over under 26mbar at 155° to 158°.

The 5-methyl-2-benzodioxolecarboxylic acid ethyl ester can also bemanufactured from homopyrocatechol in two stages as follows:

(b) While stirring under a nitrogen atomosphere, 186.2 g (1.5 mol) ofhomopyrocatechol and 236.3 g (184.3 ml, 1.5 mol) of dichloroacetic acidethyl ester are dissolved, in succession, in 1000 ml of1,2-dimethoxyethane and then 1040.2 g (7.54 mol) of pulverised potassiumcarbonate are added in portions, the temperature rising to over 50° anda thick suspension being produced. This reaction mixture is heated underreflux (bath temperature), while stirring, for 5 hours, then cooled to40° and approximately 2000 ml of water are added slowly. A brownemulsion is formed which also contains solid substance. The1,2-dimethoxyethane is distilled off in a rotary evaporator, fuller'searth is added to the black solution that remains and the whole isfiltered through diatomaceous earth. The dark-brown filtrate is adjustedto pH 2 with concentrated hydrochloric acid and, foaming vigorously, thecrude acid precipitates out in the form of a resin. The mixture isextracted three times with ethyl acetate, the combined ethyl acetatesolutions are washed twice with water, dried over sodium sulphate andconcentrated by evaporation--to leave light-brown, resin-coatedcrystals. These crystals are dissolved in approximately 700 ml of ethylacetate and the black solution is mixed with 1400 ml of saturated sodiumbicarbonate solution and, foaming gently, an emulsion is formed fromwhich the aqueous phase separates out again. This phase is extractedtwice with 300 ml of ethyl acetate each time and the ethyl acetatesolutions are in turn extracted twice with 500 ml of water each time.The aqueous phases are combined with that obtained above, adjusted to pH1 to 2 with approximately 130 ml of concentrated hydrochloric acid andextracted three times with ether. The ether solutions are each washedtwice with water, then combined and dried over sodium sulphate; fuller'searth is added and the whole is filtered and concentrated byevaporation. In order to remove any resin still present, the resultingbrown oil is extracted with 200 ml of warm cyclohexane and then 6 timeswith 100 ml of warm cyclohexane each time, the portions being decantedoff in each case. On cooling the combined portions there is obtained5-methyl-2-benzodioxolecarboxylic acid in the form of white crystalshaving a melting point of 108°-110°.

(c) 104.1 g (0.5 mol) of 5-methyl-2-benzodioxolecarboxylic acid areboiled under reflux for 15 minutes in 1000 ml of absolute ethanol thatcontains 0.5 ml of concentrated hydrochloric acid. The clear yellowsolution is then concentrated by evaporation and the residue isdissolved in a mixture of ether and 1 N sodium bicarbonate solution. Theether phase is extracted twice with water and the combined aqueousphases are in turn extracted twice with ether. The combined ether phasesare dried over sodium sulphate, filtered and concentrated byevaporation, the crude 5-methyl-2-benzodioxolecarboxylic acid ethylester remaining behind in the form of a brown oil. During subsequentdistillation the oil is distilled under reduced pressure and has aboiling point at 152° to 154° at 21 mbar. Instead of the white substancehaving a melting point of 108°-110°, it is also possible to use asstarting material the resin-coated crystals obtained under (b).

EXAMPLE 2

While stirring at 5° at 10°, 46.6 g (0.35 mol) of aluminium chloride areadded in portions over a period of 25 minutes to a solution of 31.2 g(0.15 mol) of 5-methyl-2-benzodioxolecarboxylic acid ethyl ester and28.5 g (21.3 ml, 0.18 mol) of 2-fluorobenzoyl chloride in 350 ml of1,2-dichloroethane. The reaction mixture is then stirred for a further90 minutes at 5°-10° and for 30 minutes at room temperature after whichall the aluminium chloride has dissolved. After standing at roomtemperature for approximately 24 hours, the reaction mixture is pouredonto approximately 2 kg of a mixture of ice and water. The organic phaseis separated off, washed once with 2 N hydrochloric acid, twice withwater, once with 1 N sodium bicarbonate solution and twice more withwater, then dried over sodium sulphate and concentrated by evaporationin vacuo. The crude 5-(2-fluorobenzoyl)-6-methyl-2-benzodioxolecarboxylic acid ethyl ester obtained as residue can befurther processed directly.

59 g (0.15 mol) of 5-(2-fluorobenzoyl)-6-methyl-2-benzodioxolecarboxylicacid ethyl ester are dissolved in 270 ml of ethanol and, at roomtemperature, 130 ml of 2 N sodium hydroxide solution are added, thesolution turning a dark colour and becoming slightly heated. Afterallowing to stand at room temperature for 2 hours, the ethanol isdistilled off in vacuo, there is added to the residue approximately halfits volume of water and the whole is extracted twice with ether. Theaqueous solution is then acidified with approximately 50 ml of 6 Nhydrochloric acid and the acid that separates out is extracted withethyl acetate. The organic phase is washed twice with water, dried andconcentrated by evaporation and the crude5-(2-fluorobenzoyl)-6-methyl-2-benzodioxolecarboxylic acid remains inthe form of a sand-coloured powder. For purification, it is dissolved ina small quantity of ethyl acetate, an equal volume of cyclohexane isadded and then fuller's earth is added to the hot solution and the wholeis filtered through diatomaceous earth. The filtrate is concentrated ina rotary evaporator, left to stand at room temperature and finallycooled to approximately 10°. The crystals are filtered off,recrystallised with a small quantity of ethyl acetate/cyclohexane andthen recrystallised again from ethyl acetate/cyclohexane. The substanceobtained in this manner melts at 152°-156°.

EXAMPLE 3

In a manner analogous to that described in Example 2, there is obtained,using 28.5 g (0.18 mol) of 4-fluorobenzoyl chloride,5-(4-fluorobenzoyl)-6-methyl-2-benzodioxolecarboxylic acid ethyl esterin the form of an oily crude product, and from 16.5 g (0.05 mol) of theaforementioned product there is obtained5-(4-fluorobenzoyl)-6-methyl-2-benzodioxolecarboxylic acid having amelting point of 93°-94° (from ethyl acetate).

EXAMPLE 4

In a manner analogous to that described in Example 2 there is obtained,using 34.1 g (0.2 mol) of 4-methoxybenzoyl chloride,5-(4-methoxybenzoyl)-6-methyl-2-benzodioxolecarboxylic acid ethyl ester,and from 17.1 g (0.05 mol) of the above product there is obtained5-(4-methoxybenzoyl)-6-methyl-2-benzodioxolecarboxylic acid having amelting point of 55°-57° (from ethyl acetate/petroleum ether).

EXAMPLE 5

In a manner analogous to that described in Example 2 there is obtained,using 31.2 g (0.18 mol) of (4-fluorophenyl)-acetyl chloride,5-[(4-fluorophenyl)-acetyl]-6-methyl-2-benzodioxolecarboxylic acid inthe form of an oily crude product, and from 17.2 g (0.05 mol) of theabove product there is obtained5-[(4-fluorophenyl)acetyl]-6-methyl-2-benzodioxolecarboxylic acid havinga melting point of 106°-109° (from ethyl acetate/cyclohexane).

EXAMPLE 6

While stirring at 5° to 8°, 33.3 g (0.25 mol) of aluminium chloride areadded in portions over a period of 30 minutes to a solution of 20.8 g(0.1 mol) of 5-methyl-2-benzodioxolecarboxylic acid ethyl ester and 17.7g (0.12 mol) of 2-thiophenecarbonyl chloride in 250 ml of1,2-dichlorethane. After stirring for a further 30 minutes at 5° to 8°,the cooling bath is removed and the reaction mixture is stirred for afurther 3 hours at room temperature. A further 100 ml of1,2-dichlorethane are added and the reaction mixture is poured onto amixture of 500 g of ice and 1000 ml of water. The organic phase isseparated off and washed in succession twice with 100 ml of water eachtime, once with 200 ml of 2 N sodium carbonate solution and twice morewith 100 ml of water each time. The aqueous phase, on the other hand, isextracted twice with 100 ml of chloroform each time and the residue fromthese extracts is combined with the organic phase. The latter is thendried with sodium sulphate, filtered and concentrated by evaporation invacuo. The residue is chromatographed over a column of 1000 g of silicagel using chloroform/petroleum ether/ethyl acetate in a ratio of 10:10:1as solvent and eluant. After approximately 10% of the total quantity offirst-run products, the desired5-methyl-5-[(2-thienyl)-carbonyl]-2-benzodioxolecarboxylic acid ethylester is eluted as a main product of approximately 80%. The appropriatefractions crystallise spontaneously and can be used directly for thenext stage. A small quantity of petroleum ether and ethyl acetate isadded to a sample and the resulting crystal suspension is filtered. Thecrystals of the above ester obtained in this manner melt at 69°-70°.

15.9 g (0.05 mol) of5-methyl-6-[(2-thienyl)carbonyl]-2-benzodioxolecarboxylic acid ethylester are dissolved in 160 ml of ethanol while heating to approximately60° and 75 ml of 2 N sodium hydroxide solution are added, whilestirring, to the solution which has been cooled again to roomtemperature. After stirring for 15 minutes at approximately 20°, theethanol is evaporated off in vacuo, a small quantity of fuller's earthis added to the solution that remains and the whole is filtered and 90ml of 2 N hydrochloric acid are added thereto. The acid that separatesout is extracted with approximately 300 ml of ethyl acetate, the ethylacetate solution is washed twice with 150 ml of water each time and theaqueous phases are again extracted with ethyl acetate. The combinedorganic phases are dried with sodium sulphate, filtered and concentratedand the desired product crystallises. The product is filtered off andrecrystallised from ethyl acetate. The 5-methyl-6-[(2-thienyl)-carbonyl]-2-benzodioxolecarboxylic acid obtained in thismanner melts at 136°-137°.

EXAMPLE 7

A mixture of 4.05 g (0.015 mol) of1-(4,5-dihydroxy-2-methylphenyl)-2-methyl-2-phenyl-1-propanone, 2.83 g(0.018 mol) of dichloroacetic acid ethyl ester and 5.6 g (0.04 mol) ofanhydrous potassium carbonate is stirred in 15 ml of dimethylformamideat 90° under a nitrogen atmosphere for 2 hours. As much of thedimethylformamide as possible is then evaporated off in a rotaryevaporator. The residue is dissolved in 100 ml of water and the solutionis left to stand at room temperature for 1 hour. It is then renderedacidic to Congo Red with dilute hydrochloric acid, and the5-methyl-6-(2-methyl-2-phenylpropionyl)-2-benzodioxolecarboxylic acidthat is liberated is extracted with ethyl acetate and the resultingsolution is concentrated by evaporation. Recrystallisation of theresidue yields the pure carboxylic acid in the form of small colourlessneedles having a melting point of 117°-119°.

The dihydroxyketone required is manufactured as follows:

(a) While stirring, 80.0 g (0.6 mol) of aluminium chloride are added inportions to a solution of 84.1 g (0.5 mol) of1,2-dimethoxy-4-methylbenzene (homopyrocatechol dimethyl ether or4-methylveratrole) in 750 ml of 1,2-dichloroethane, the temperaturebeing maintained at a maximum of 20° by cooling in an ice bath. Then, at15°-20°, 85.0 g (approximately 73 ml, 0.55 mol) of phenylacetyl chlorideare added dropwise over a period of one hour, a moderate evolution ofhydrogen chloride occurring and the aluminium chloride being dissolved.

The reaction mixture is then stirred at room temperature for a further 6hours and then poured onto 3000 ml of a mixture of ice and water. Theresulting layers are separated and the organic phase is washed insuccession with 2 N hydrochloric acid, twice with water, then with 1 Nsodium bicarbonate solution and twice more with water, dried, filteredand concentrated by evaporation. The partly crystallised residue iscaused to crystallise completely from ether/petroleum ether (boilingrange 40°-65°) yielding the1-(4,5-dimethoxy-2-methylphenyl)-2-phenyl-1-ethanone having a meltingpoint of 45°-48°.

(b) While stirring at room temperature, a solution of 13.5 g (0.05 mol)of 1-(4,5-dimethoxy-2-methylphenyl)-2-phenyl-1-ethanone and 21.3 g (9.35ml, 0.15 mol) of methyl iodide in 135 ml of methylene chloride is addeddropwise over a period of 45 minutes to 100 ml of a 40% solution oftetrabutylammonium hydroxide (approximately 0.15 mol). A moderatelyexothermic reaction heats the reaction mixture to approximately 35°. Thereaction mixture is then stirred for a further 10 hours without heatingor cooling. The phases are then separated and the organic phase iswashed twice with water, dried over sodium sulphate, filtered andconcentrated by evaporation. 300 ml of ether are added to the residueand the tetrabutylammonium iodide crystallises out. This is filtered offand the filtered material is washed with ether. The filtrate isconcentrated by evaporation and the above residue is dissolved in amixture of petroleum ether (boiling range 40°-60°), chloroform and ethylacetate 10:10:1 and adsorbed on 450 g of silica gel. Elution with theafore-mentioned mixture and concentration of the first 4 liters ofeluate by evaporation yields1-(4,5-dimethoxy-2-methylphenyl)-2-methyl-2-phenyl-1-propanone in theform of an oil which can be further used directly.

(c) 8.0 g of the oily product of (b) (approximately 0.026 mol) are mixedwith 50 g of pyridine hydrochloride and the mixture is heated at 200°(internal temperature) for 4 hours. The reaction mixture is then allowedto cool, ice and 50 ml of 2 N hydrochloric acid are added and thereaction product that separates out is extracted with ethyl acetate.Concentrating the resulting solution by evaporation and recrystallisingthe partly crystallised residue from ethyl acetate/cyclohexane yields1-(4,5-dihydroxy-2-methylphenyl)-2-methyl-2-phenyl-1-propanone having amelting point of 189°-191°.

EXAMPLE 8

A solution of 71.0 g (0.24 mol) of5-benzoyl-6-methyl-2-benzodioxolecarboxylic acid (melting point120°-122°, cf. Example 1), in 200 ml of acetonitrile and a solution of41.2 g (0.25 mol) of D-ephedrine (base) in 300 ml of acetonitrile, eachat approximately 30°, are combined and cooled in an ice bath and thecrystals that are deposited are filtered off. The resulting crystalfraction is recrystallized four times from acetonitrile, yielding theD-ephedrine salt of (+)-5-benzoyl-6-methyl-2-benzodioxolecarboxylic acidin the form of colourless, fine needles having a melting point of149°-150° (sinters from 145°).

Dissolving in water, acidifying with 2 N hydrochloric acid and filteringoff yields the corresponding free acid which, after crystallisation from50 ml of ethyl acetate with the addition of 20 ml of petroleum ether,(boiling range 40°-60°), melts at 145°-147°; [α]_(D) ²⁰ +67° (c=1% inacetone).

The carboxylic acid is freed and separated off from the mother liquorresidues of the above crystallisation operations and reacted inanalogous manner in the form of a solution in acetonitrile with thecorresponding solution of L-ephedrine. The salt of L-ephedrine with the(-)-5-benzoyl-6-methyl-2-benzodioxolecarboxylic acid, obtained as acrude product, is, also in analogous manner, first recrystallised fourtimes from acetonitrile and then the carboxylic acid is freed from theresulting pure salt which has a melting point of 149°-150° (sinters from145°). The melting point of the carboxylic acid, after recrystallisationfrom ethyl acetate/petroleum ether (see above), is 145°-147°, [α]_(D) ²⁰-67°±1° (c=1% in acetone).

EXAMPLE 9

A suspension of 46.7 g (0.338 mol) of freshly calcined potassiumcarbonate in 180 ml of 1,2-dimethoxyethane is stirred for 10 minutesunder nitrogen in a high-speed agitator. Then, while stirring normally,15.7 g (67.6 mmol) of (4,5-dihydroxy-2-fluorophenyl)-phenylmethanone and10.6 g (67.6 mmol) of dichloroacetic acid ethyl ester are added and themixture is heated to 70°. After 6 hours, an additional 3.9 g (20 mmol)of dichloroacetic acid ethyl ester are added and the mixture is boiledfor a further 15 hours. Water is then added and the whole is adjusted topH 1-2 with hydrochloric acid, partially concentrated by evaporation invacuo and extracted with ethyl acetate. The organic phases are washedwith water and saturated sodium chloride solution, dried over sodiumsulphate and concentrated completely by evaporation. The residue isesterified with ethanol/p-toluenesulphonic acid. The ester is purifiedby chromatography on silica gel using an ethyl acetate/n-hexane mixture(ratio 1:1) as eluant. After concentrating the appropriate fractions byevaporation, the ester is dissolved in methanol and hydrolysed with 1 Nsodium hydroxide solution at room temperature. Ice/water is added to thereaction mixture and the whole is acidified and extracted with ethylacetate. The combined ethyl acetate extracts are washed, dried andconcentrated by evaporation. The yellow residue is boiled up withn-hexane and filtered with suction. After recrystallising the filteredmaterial twice from 1,2-dichloroethane, the5-benzoyl-6-fluoro-2-benzodioxolecarboxylic acid is obtained in the formof white crystals having a melting point of 152°-153.5°.

The (4,5-dihydroxy-2-fluorophenyl)-phenylmethanone required can bemanufactured as follows:

(a) Six bomb tubes, each containing 4.8 g (30.0 mmol) of4-fluoro-1,2-dimethoxybenzene (obtained from 3,4-dimethoxyaniline by aBalz-Schiemann reaction), 7.5 g (37.5 mmol) of (2-pyridinyl)-benzoateand 300 ml of trifluoroacetic acid, are heated at 100° for 41/2 hourswhile stirring magnetically. The contents of all six bomb tubes ispoured into 600 ml of water while stirring vigorously and the solidsubstance that separates out is filtered with suction. The filtrate isextracted several times with toluene. The solid substance is dissolvedin the combined toluene extracts. The toluene solution is washed withwater and saturated sodium chloride solution, dried over magnesiumsulphate and concentrated to dryness by evaporation. The resultingsemi-solid oil is dissolved in 500 ml of warm isopropanol and treatedwith carbon. The filtered solution is concentrated in vacuo untilcrystallisation begins. After complete crystallisation, the(4,5-dimethoxy-2-fluorophenyl)-phenylmethanone is filtered with suctionand washed with cold isopropanol, yielding white crystals having amelting point of 102°-104°.

The same substance can also be manufactured as follows:

(b) 12.7 g (95 mmol) of aluminium trichloride in 80 ml of1,2-dichloroethane are stirred under nitrogen and cooled to 3°. 13.35 g(95 mmol) of benzoyl chloride are added. At 3°, this red solution isadded dropwise over a period of 25 minutes to a solution of 12.55 g(80.3 mmol) of 1,2-dimethoxy-4-fluorobenzene (4-fluoroveratrole) in 80ml of 1,2-dichloroethane. The reaction mixture is stirred for a further3 hours at 3°, then for 31/2 hours at room temperature and then pouredonto a mixture of 250 ml of ice and 20 ml of concentrated hydrochloricacid. The organic phase is separated off and the aqueous phase isextracted several times with ether. Organic phase and ether solutionsare combined, washed with 1 N sodium hydroxide solution, water and withsaturated sodium chloride solution, dried over magnesium sulphate andconcentrated by evaporation. The resulting yellow oil is stirred with 50ml of ether in an ice bath until crystallisation takes place, yieldingthe desired (4,5-dimethoxy-2-fluorophenyl)-phenylmethanone in the formof white crystals having a melting point of 102°-103°.

For demethylation, a mixture of 21.0 g (80.7 mmol) of(4,5-dimethoxy-2-fluorophenyl)-phenylmethanone, 80 ml of glacial aceticacid and 80 ml of hydrobromic acid (48%) is boiled under reflux for 17hours. The reaction mixture is then poured onto ice/water and extractedseveral times with ethyl acetate. The combined extracts are washed withwater and saturated sodium chloride solution, treated with activatedcarbon, dried over sodium sulphate and concentrated to dryness byevaporation. The residue is recrystallised twice from 1,2-dichloroethaneyielding the (4,5-dihydroxy-2-fluorophenyl)-phenylmethanone having amelting point of 169.5°-171°.

EXAMPLE 10

A suspension of 83 g (0.60 mol) of freshly calcined potassium carbonatein 250 ml of 1,2-dimethoxyethane is stirred for 10 minutes undernitrogen with a high-speed agitator. Then, while stirring normally,28.10 g (0.113 mol) of (4,5-dihydroxy-2-chlorophenyl)-phenylmethanoneand 19.5 g (0.124 mol) of dichloroacetic acid ethyl ester are added. Thereaction mixture is boiled under reflux for 20 hours, then 400 ml ofwater are added and the whole is stirred for a further 1 hour. A portionof the solvent is evaporated off in vacuo and the aqueous phase isextracted several times with ethyl acetate. The organic extracts arecombined, washed with water and saturated sodium chloride solution,treated with activated carbon, dried over magnesium sulphate andconcentrated by evaporation. The resulting brown oil is chromatographedon silica gel using the eluant chloroform/methanol/concentrated ammonia22:7:1. The fractions containing the uniform substance are combined,partially concentrated by evaporation, acidified with 1 N hydrochloricacid and extracted with ethyl acetate. The organic phases are washed,dried and concentrated by evaporation as mentioned above. The resultingyellow oil is triturated with hot hexane until crystallisation takesplace. The crystals are filtered off and triturated a second time withhot hexane. There is thus obtained the desired5-benzoyl-6-chloro-2-benzodioxolecarboxylic acid in the form of a whitepowder having a melting point of 146°-148°.

The (4,5-dihydroxy-2-chlorophenyl)-phenylmethanone required as startingmaterial can be manufactured by two methods:

(a) A mixture of 300 ml of carbon disulphide, 80 g (0.60 mol) ofpowdered aluminium trichloride and 28.9 g (0.20 mol) of2-chloro-1,2-benzenediol is stirred for 15 minutes at room temperatureand then for 1 hour at 40°. 30.9 g (0.220 mol) of benzoyl chloride arethen added over a period of 10 minutes and the whole is stirred for afurther 15 minutes at 40° and heated in order slowly to distil off thecarbon disulphide. The dry residue is then heated to 140° (bathtemperature) in the course of 1 hour and maintained at this temperaturefor 31/2 hours. The brown solid mass is cooled, 300 ml of 3 Nhydrochloric acid and 200 ml of ethyl acetate are added and the mixtureis stirred until completely dissolved. The organic phase is separatedoff and the aqueous phase is extracted with ethyl acetate. The combinedorganic phases are washed with water and saturated sodium chloridesolution, dried over sodium sulphate, treated with carbon andconcentrated by evaporation. The dark-brown residue is dissolved in 100ml of 1,2-dichloroethane, 105 ml of n-hexane are added and the whole istriturated until crystallisation takes place. The crystals are filteredwith suction and recrystallized from dichloroethane/hexane. The(2-chloro-4,5-dihydroxyphenyl)phenylmethanone, obtained in the form ofwhite crystals (melting point 130°-135°), can be further reacteddirectly.

(b) The afore-mentioned dihydroxyketone can also be obtained in twostages analogously to Example 9(a) and (b). The(2-chloro-4,5-dimethoxyphenyl)-phenylmethanone required for this purposecan be obtained by acylating 4-chloro-1,2-dimethoxybenzene with benzoylchloride in the presence of iodine. It is easier to obtain, however, ifone equivalent of 4-chloro-1,2-dimethoxybenzene is heated in a bomb tubeat 150° for 2 hours with 1.1 equivalents of (2-pyridinyl)-benzoate intrifluoroacetic acid. After working up and demethylation in a manneranalogous to Example 9(b), the desired(4,5-dihydroxy-2-chlorophenyl)phenylmethanone is obtained.

EXAMPLE 11

Tablets containing 100 mg of 5-benzoyl-6-methyl-2-benzodioxolecarboxylicacid can be manufactured, for example, having the following composition:

    ______________________________________                                        Composition             per tablet                                            ______________________________________                                        5-benzoyl-6-methyl-2-benzo-                                                                           100    mg                                             dioxolecarboxylic acid                                                        lactose                 50     mg                                             wheat starch            73     mg                                             colloidal silica        13     mg                                             talc                    12     mg                                             magnesium stearate      2      mg                                                                     250    mg                                             ______________________________________                                    

MANUFACTURE

The active ingredient is mixed with lactose, a portion of the wheatstarch and with colloidal silica and the mixture is forced through asieve. A further portion of the wheat starch is made into a paste with 5times the quantity of water on a water bath and the powder mixture iskneaded with this paste until a slightly plastic mass is formed. Themass is forced through a sieve of approximately 3 mm mesh width anddried and the dry granulate is again forced through a sieve. Theremainder of the wheat starch, the talc and the magnesium stearate arethen admixed. The resulting mixture is pressed into 250 mg tabletshaving (a) breaking notch(es).

EXAMPLE 12

For the manufacture of 1000 capsules, each containing 100 mg of activeingredient, 100 g of 5-benzoyl-6-methyl-2-benzodioxolecarboxylic acidare mixed with 173.0 g of lactose, and the mixture is moistened evenlywith an aqueous solution of 2.0 g of gelatine and granulated through asuitable sieve (for example sieve III according to Ph. Helv. V.). Thegranulate is mixed with 10.0 g of dried maize starch and 15.0 g of talc,and 1000 size 1 hard gelatine capsules are filled with equal quantitiesof this mixture.

Instead of 5-benzoyl-6-methyl-2-benzodioxolecarboxylic acid it is alsopossible to use in the above Examples a different compound of thegeneral formula I or a pharmaceutically acceptable salt of a compound ofthe general formula I that is capable of salt formation, for example oneof the compounds described in Examples 2 to 8, or a pharmaceuticallyacceptable salt of such a compound.

What is claimed is:
 1. A benzodioxole derivative of the formula I##STR12## in which R₁ represents phenyl, thienyl or furyl, each of whichis unsubstituted or substituted by lower alkyl, lower alkoxy orhalogen,alk represents an alkylene or alkylidene radical having amaximum of 5 carbon atoms, n represents 0 or 1, R₂ and R₃ eachrepresents, independently of the other, hydrogen, lower alkyl, loweralkoxy or halogen, and A represents the radical O--R₄, wherein R₄represents hydrogen or lower alkyl, or A represents the radical##STR13## in which either R₅ and R₆ each represents, independently ofthe other, hydrogen or lower alkyl, or R₅ and R₆ are bonded to oneanother and, together with the adjacent nitrogen atom, representunsubstituted or lower alkyl-substituted tetra- to hexamethyleneimino or4-morpholinyl, in the form of racemates or optical antipodes, and thesalts of a compound of the formula I in which A represents OR₄ whereinR₄ represents hydrogen, with bases, and the acid addition salts of acompound of the formula I in which the radical R₁ has a basic character.2. A compound of the formula I given in claim 1 in which R₁ representsphenyl, thienyl or furyl, each of which is unsubstituted or substitutedby lower alkyl, lower alkoxy or halogen, alk represents alkylene oralkylidene having a maximum of 3 carbon atoms, R₂ represents lower alkylor halogen, R₃ represents hydrogen, lower alkyl or halogen, and n and Ahave the meanings given in claim 1, in the form of racemates or opticalantipodes, and salts of such a compound in which A represents OR₄wherein R₄ is hydrogen, with bases.
 3. A compound of the formula I givenin claim 1 in which R₁ represents phenyl or thienyl, each of which isunsubstituted or substituted by lower alkyl, lower alkoxy or halogen,alk represents methylene, n represents 0 or 1, R₂ represents lower alkylor halogen, R₃ represents hydrogen or lower alkyl, and A represents OR₄wherein R₄ represents hydrogen or lower alkyl, in the form of racematesor optical antipodes, and the pharmaceutically acceptable salts of sucha compound in which R₄ represents hydrogen, with bases.
 4. A compound ofthe formula I given in claim 1 in which R₁ represents phenyl that isunsubstituted or substituted by lower alkyl, lower alkoxy or halogen,alk represents methylene, n represents 0 or 1, R₂ represents lower alkylor halogen, R₃ represents hydrogen or lower alkyl, and A represents OR₄wherein R₄ represents hydrogen or lower alkyl, in the form of racematesor optical antipodes, and the pharmaceutically acceptable salts of sucha compound in which R₄ is hydrogen, with bases.
 5. A compound of theformula I given in claim 1 in which R₁ represents phenyl that isunsubstituted or substituted by lower alkyl, lower alkoxy or halogen, nrepresents 0, R₂ represents lower alkyl or halogen, R₃ representshydrogen, and A represents OR₄ wherein R₄ represents hydrogen or loweralkyl, and the acyl radical is bonded in the 5- or 6-position, in theform of racemates or optical antipodes, and the pharmaceuticallyacceptable salts of such a compound in which R₄ represents hydrogen,with bases.
 6. A compound according to claim 5 which is5-benzoyl-6-methyl-2-benzodioxolecarboxylic acid, its optical antipodesand its pharmaceutically acceptable salts with bases.
 7. A compoundaccording to claim 5 which is5-(4-fluorobenzoyl)-6-methyl-2-benzodioxolecarboxylic acid and itspharmaceutically acceptable salts with bases.
 8. A compound according toclaim 5 which is 5-(4-methoxybenzoyl)-6-methyl-2-benzodioxolecarboxylicacid and its pharmaceutically acceptable salts with bases.
 9. A compoundaccording to claim 5 which is5-[(4-fluorophenyl)-acetyl]-6-methyl-2-benzodioxolecarboxylic acid andits pharmaceutically acceptable salts with bases.
 10. A compoundaccording to claim 5 which is5-methyl-6-[(2-thienyl)-carbonyl]-2-benzodioxolecarboxylic acid and itspharmaceutically acceptable salts with bases.
 11. A compound accordingto claim 5 which is 5-benzoyl-6-fluoro-2-benzenedioxolecarboxylic acidand its pharmaceutically acceptable salts with bases.
 12. A compoundaccording to claim 5 which is5-benzoyl-6-chloro-2-benzodioxolecarboxylic acid and itspharmaceutically acceptable salts with bases.
 13. A pharmaceuticalcomposition having diuretic activity comprising a therapeuticallyeffective amount of a compound according to claim 1 or of apharmaceutically acceptable salt of a compound according to claim 1 thatis capable of salt formation, together with at least one pharmaceuticalcarrier.
 14. A pharmaceutical composition having diuretic activitycomprising a therapeutically effective amount of a compound according toclaim 2 or of a pharmaceutically acceptable salt of such a compound inwhich A represents OR₄ wherein R₄ is hydrogen, with a base, togetherwith at least one pharmaceutical carrier.
 15. A pharmaceuticalcomposition having diuretic activity comprising a therapeuticallyeffective amount of a compound according to claim 3 or of apharmaceutically acceptable salt of such a compound in which Arepresents OR₄ wherein R₄ is hydrogen, with a base, together with atleast one pharmaceutical carrier.
 16. A pharmaceutical compositionhaving diuretic activity comprising a therapeutically effective amountof a compound according to claim 4 or of a pharmaceutically acceptablesalt of such a compound in which A represents OR₄ wherein R₄ ishydrogen, with a base, together with at least one pharmaceuticalcarrier.
 17. A pharmaceutical composition having diuretic activitycomprising a therapeutically effective amount of a compound according toclaim 5 or of a pharmaceutically acceptable salt of such a compound inwhich A represents OR₄ wherein R₄ is hydrogen, with a base, togetherwith at least one pharmaceutical carrier.
 18. A pharmaceuticalcomposition having diuretic activity comprising a therapeuticallyeffective amount of the compound according to claim 6 or of apharmaceutically acceptable salt thereof with a base, together with atleast one pharmaceutical carrier.
 19. A method for treating oedema orhypertension in a mammal comprising administering to said mammal atherapeutically effective amount of a compound according to claim 1 orof a pharmaceutically acceptable salt of a compound according to claim 1that is capable of salt formation.
 20. A method for treating oedema orhypertension in a mammal comprising administering to said mammal atherapeutically effective amount of a compound according to claim 2 orof a pharmaceutically acceptable salt of such a compound in which Arepresents OR₄ wherein R₄ is hydrogen, with a base.
 21. A method fortreating oedema or hypertension in a mammal comprising administering tosaid mammal a therapeutically effective amount of a compound accordingto claim 5 or of a pharmaceutically acceptable salt of such a compoundin which A represents OR₄ wherein R₄ is hydrogen, with a base.
 22. Amethod for treating oedema or hypertension in a mammal comprisingadministering to said mammal a therapeutically effective amount of thecompound according to claim 6 or of a pharmaceutically acceptable saltthereof with a base.